Skin depigmentation

ABSTRACT

The specification discloses that synergistic compositions for depigmentation by topical application have been found which comprise a mixture of hydroquinone, retinoic acid and a corticosteroid formulated in a pharmaceutically-cosmetically acceptable vehicle. An illustrative composition comprising from about 2 percent to about 5 percent hydroquinone, from about 0.05 percent to about 0.1 percent retinoic acid and from about 0.05 percent to about 0.1 percent dexamethasone was particularly effective.

Ilnited States Patent ltligman [4 Dec. 24, 1974 [54] SKIN DEPIGMENTATION[76] Inventor: Albert Montgomery Kligman, 1940 Lombard St.,Philadelphia, Pa. 19146 Filed: Jan. 22, 1973 Appl. No.2 325,687

Related [1.8. Application Data [56] References Cited UNITED STATESPATENTS 10/1961 Pommer et al. 2601413 10/1962 Tamwse-mmrW TZT: ..424/62OTHER PUBLICATIONS Wells et al., Cosmetics and the Skin, (1964-), pages109 and 609.

The Merck Index 7th edition, (1960), page 1097.

Primary Examiner-Sam Rosen Attorney, Agent, or FirmJames Magee, Jr.

[57] ABSTRACT The specification discloses that synergistic compositionsfor depigmentation by topical application have been found which comprisea mixture of hydroquinone, retinoic acid and a corticosteroid formulatedin a pharmaceutically-cosmetically acceptable vehicle. An illustrativecomposition comprising from about 2 percent to about 5 percenthydroquinone, from about 0.05 percent to about 0.1 percent retinoic acidand momenta? 0.05 percent to about 0.1 percent dexamethasone wasparticularly effective.

8 Claims, No Drawings skin DEPIGMENTATION CROSS REFERENCE TO RELATEDAPPLICATION This application is a continuation-in-part of copendingapplication Ser. No. 49,523, filed June 24, 1970, now abandoned.

BACKGROUND OF THE INVENTION 1. Field of the Invention This inventionrelates to a synergistic and nonsensitizing composition fordepigmentation of mammalian skin for use by topical application.

2. Description of the Prior Art So-called compositions for bleachingskin have been known for many years. The use of hydroquinone and itsderivatives as agents in bleaching creams is shown in the followingpublications:

a. U.S. Pat. No. 3,060,097, issued Oct. 23, 1962 to a skin-bleachingcomposition comprising sodium hypochlorite, hydroquinone monobenzylether and a penetrant. Three British Pat. Nos. 763,029, 856,431 and965,869 issued to the same inventor on similar compositions.

b. French Pat. No. 1,513,395, issued Jan. 8, 1968 to a skin-bleachingcomposition comprising hydroquinone monobenzyl ether or a derivativethereof in combination with tyrothricin or a derivative thereof.

c. French Pat. No. 1,270,854, issued July 24, 1961 to a skin-bleachingcomposition comprising hydroquinone benzyl ether (lether debenzylhydroquinone) and an anti-oxidant. The product may be formulatedto contain vitamins, amino acids, cholesterol, etc.

d. U.S. Pat. Nos. 2,274,725 (Mar. 3, 1942), 2,376,884 (May 29, 1945) and2,377,188 (May 29, 1945) are to sunscreen preparations comprisinghydroquinone as the active sunfilter agent. These preparations arestabilized by the addition of certain antioxidants.

e. Zschr. l-laut-GeschL-Krkh. 42, 17: 711-716 reports studies ofbleaching the skin using hydroquinone monobenzyl ether. When a subjectwas found to have sensitive skin, percent hydroquinone monobenzyl etherand 4 percent prednisolone was used to prevent or control the contactdermatitis produced by the hydroquinone monobenzyl ether. No mention ismade of an improved bleaching effect when the preparation containedprednisolone.

f. Some other articles reporting on skin-bleaching by the use ofhydroquinone or its derivatives are:

1. Archives of Dermatology, 84, No. 1 131-184 (July, 1961).

respect to depigmentation and essentially nonsensitizing to the skin.These compositions comprise hydroquinone or a nonsensitizing derivativethereof, retinoic acid, and a corticosteroid.

The composition is used by applying, preferably on a regular treatmentschedule to the area of skin to be treated until relatively complete andpermanent depigmentation is achieved. The composition can be applied tothe skin with or without any dressing but occlusive dressing has beenfound to facilitate depigmentation. In general, the depigmentation isreversible and cessation v of treatment may lead to repigmentationunless a sus- 2. Clinical Medicine, 70, No. 6, 1111-1114 (June,

SUMMARY OF THE INVENTION Broadly stated the instant invention isconcerned with a method for lightening or depigmenting mammalian skinand to compositions which are synergistic with taining regimen totreatment is continued. Such a regimen may include less frequentapplication ofthe herein disclosed composition or daily treatment withhydroquinone alone.

It has long been desirable that certain skin disorders or diseases ofthe skin be treated to reduce hyperpigmentation generally caused by thedeposition of excess quantities of melanin. This hyperpigmentation isgenerally viewed as cosmetically undesirable and psychologicallydisabling. Examples of such hyperpigmentation include freckles, senilelentigo, lentigines (liver spots), melasma, contact allergypigmentation, vitiligo, sunburn pigmentation, post-inflammatoryhyperpigmentation due to abrasion, burns, wounds, dermatitis, phototosicreaction and other similar small, fixed pigmented lesions. It is alsooften desirable to decolorize normally pigmented skin to generallyincrease fairness of appearance or to blend hypopigmented areas intosurrounding normal skin, for example in the treatment of generallydarkskinned people suffering from vitiligo.

It is an object of this invention to provide an effective treatment forhyperpigmentation of-skin.

Another object of the invention is to provide compositions which do notinduce sensitization reactions in subjects treated forhyperpigmentation.

A further object of the invention is to provide an effective method forreduction of melanin levels in the tissue in both hyperpigmented andnormally pigmented skin.

A still further object of the invention is to provide compositions whichcan effectively reduce pigmentation by a process which involves eitheror both the production of melanin or its transfer but without damage tothe melanoblasts themselves.

These and other related objects are achieved by the compositions of thisinvention which comprise retinoic acid, a corticosteroid, and adepigmentation agent which operates by interfering with or inhibitingthe normal pigmentation process. More specifically, a compositioncomprising retinoic acid, hydroquinone, and a corticosteroid has beenfound to be particularly effective in achieving a controllable degree ofdepigmentation of both hyperpigmentated and normally pigmented skin.Depigmentation is controllable to the extent that pigmentation innormally pigmented skin can be preserved at the normal level thusallowing blending of normal and hyperpigmented areas.

Compounds heretofore known as skin bleaching agents includehydroquinone, hydroquinone monoethyl ether, hydroquinone monobenzylether, ammoniated mercury, zinc peroxide, mercurous chloride andbichloride of mercury. These compounds are associated with disadvantageswhich include sensitization, ineffectiveness, irritation and lack ofpredictable results.

73, No. 3, 87-88 [Mar., 1966] wherein 35 percent of those subjectstreated showed excellent results, 5 percent good, 35 percent fair and 25percent poor.

Moreover, combinations of a corticosteroid such as dexamethasone andhydroquinone even under occlusion did not provide completedepigmentation after 6 to 8 weeks of twice-daily treatment. Similarly,the combination of hydroquinone and retinoic acid was ineffective toprovide complete depigmentation, i.e., less pigmentation than isnormally present in persons having white skin.

Other compounds capable of causing exfoliation of skin was substitutedfor retinoic acid but were not effective in achieving completedepigmentation.

Corticosteroids which can be used include those usually used in thetopical treatment of skin conditions. 11- lustrative compounds includecorticosteroids selected from the group comprising hydrocortisone,cortisone, prednisolone, prednisone, dexamethasone, betamethasone,fluocinolone acetonide, triamcinolone, fluocinolone, triamcinoloneacetonide, methylprednisolone, fluorometholone, or an ester thereof whenchemically possible, formulated in a pharmaceuticallycosmeticallyacceptable vehicle. Esters of corticosteroids are disclosed in US. Pat.Nos. 3,694,471; 3,152,154; and 3,147,249.

Subsequent investigations to improve depigmenta tion has unexpectedlyshown that a composition containing hydroquinone, dexamethasone, andretinoic acid produced good to excellent results in essentially all ofthe subjects treated. Results equivalent to those obtained with thecombination can not be achieved by any of the individual componentsalone.

The compositions of the present invention are applied according to thefollowing general regimen: 1n the case of the formulation ofexample 1,the composition was applied two to three times daily to the areas to bebleached. The composition is preferably applied three times a day for 2days, then two times a day till irritation (mild inflammation) can beseen. Depending upon the degree of irritation, the composition isapplied once or twice a day till depigmentation occurs. Depigmentationusually begins to occur 5 to 21 days after the initial application.Depigmentation is usually complete within 6 to weeks.

In patients with recurrent or permanent hyperpigmentation (Negroes,other dark-skinned races), depigmentation can be maintained by severalapplications per week.

The results produced by the application of the above composition areexceptionally good. In almost 100 percent of the subjects so treated,good to excellent depigmentation was obtained. The results wereparticularly dramatic in normal Negro skin, whereon the skin wasbleached white in the majority of subjects so treated.

The active ingredients ofthis composition can be formulated into anycosmetically or pharmaceutically acceptable vehicle or base. Suchvehicle formulations are well-known and are disclosed in the literature,e.g., in Cosmetics and The Skin by Wells and Lubowe. Reinhold PublishingCorporation. N.Y., 1964. A particularly suitable vehicle comprises a 1to 1 mixture ofethanol and propylene glycol and may also include astabilizer, perfumes and other usual adjuants.

The following examples illustrate formulations of hydroquinone, retinoicacid and suitable corticosteroid.

EXAMPLE 1 Hydroquinone 2% Retinoic Acid 0.0571 Fluorometholonc 0.0257:

Fragrance q.s. Propylene glycol Ethanol it q.s. ad ml.

Finely pulverize the hydroquinone, retinoic acid and fluorometholone anddissolve in about 80 ml. of the 50:50 mixture ofpropylene glycol andethanol. Add the fragrance and q.s. ad to 100 ml. Mix well and apply toarea to be bleached.

EXAMPLE 2 Substitution in the formula of Example 1 for thefluorometholone used therein of 0.025 percent of desamethasone producesan equivalent formulation.

EXAMPLE 3 Hydroquinone 271 Retinoic acid 0.05% Fluorometholone 0.025%

Vanishing Cream base q.s. as 100 gm.

Finely pulverize the hydroquinone, retinoic acid and fluorometholone.Add a small quantity of the vanishing cream base and mix well to obtaina gritless paste. Add additional vanishing cream base to make 100 gm. ofproduct. Mix well and apply.

EXAM PLE 4 Hydroquinone 2'71 Retinoic acid 0.05'7: Fluorometholone0.025%

Emolient lotion q.s. ad 100 ml.

Finely pulverize the hydroquinone, retinoic acid and fluorometholone.Add a small quantity of the emolient lotion to the powder to make agritless paste. Add sufficient lotion to make 100 ml. Mix well andapply.

EXAMPLE 5 Hydroquinone 271 Retinoic acid 0.05% Hydrocortisone 2.571

Vanishing cream base q.s. ad 100 gm.

This formulation was prepared according to Example 3.

EXAMPLE 6 Hydroquinone 5% -Continued Retinoic acid FluoromethononeVanishing cream base q.s. ad 100 gm.

This formulation was prepared according to Example 5 3.

A particularly preferred formulation for depigmentation was found, bytrial and error, to comprise dexamethasone about 0.1 percent, retinoicacid about 0.1 percent, and hydroquinone about 5.0 percent in ahydrophillic ointment (V.S.P.) base to make 100 percent by weight. Thiscomposition was found to regularly depigment black skin when used twicedaily for a period of 4 to 5 weeks. l5

In general, it has been found that effective formulations having anunexpected degree of activity can contain from about I to about 5 weightpercent hydroquinone and preferably from about 2 to about 5 weightpercent hydroquinone.

The amount of retinoic acid can range from about 0.05 to about 2 percentby weight with the preferred range being from about 0.05 to about 0.1weight per cent.

Similarly the amount of corticosteroid can range from about 0.05 toabout 2 weight percent depending on the particular steroid used. In apreferred formulation dexamethasone in amounts of from about 0.05 toabout 0.1 weight percent has been found to give excellent results.

In a series of clinical studies, 69 patients with melasma were treatedwith topical preparations identified as A, B and C in a double blindmanner. The composition of preparations A, B and C are set forth below.

Preparation A Preparation B 2% hydroquinone 2% hydroquinone. 0.05%retinoic acid, and 0.05% dexamethasone 5% hydroquinone.

0.l'7z retinoic acid, and OM71 dexamethasone Preparation C Table l A B CExcellent 3 l0 9 Good 2 3 7 Fair 8 l 3 Poor 4 3 l Incomplete 6 6 3 TableII shows the total number of subjects falling into the excellent andgood classes and the corresponding percentage for these completing thestudy for each composition.

These results indicate that the presence of retinoic acid anddexamethasone unexpectedly increase the degree of depigmentation whichcan be achieved by the hydroquinone and that increasing the amounts ofthe active ingredients above the level of composition B does not greatlyalter the results.

Some of the topical medication used in the above study invoked moderateirritation. This irritation was present within the first 1 to 4 days ofuse of medication and became more severe with continued twice a dayapplication. Those patients who discontinued the medication for l to 2days and then gradually resumed use of the topical medication at oncedaily or occasionally twice daily, were able to tolerate the medication.Although in some patients the inflammation continued throughout thestudy it could be easily managed by occasionally skipping a day of useof the medication or reducing the frequency of use to once a day. Manyof the patients who noted inflammation believed that the improvement orlightening of the skin followed soon after the period of inflammation.Those patients who made this observation were therefore motivated tocontinue the use of the medication and these patients seemed to improvemore than the other subjects. Most patients who improved did so duringthe second and third week of use of the medication, although some didnot improve unitl after the 6th week.

There were no incidences of contact dermatitis, allergic manifestationsto medicine, or idiosyncratic reactions. The only side effect was theinflammation discussed above. In all cases the inflammation was quicklyreversible with discontinuation of the medication. At its worst itconsisted of erythema, itching, minimal desqualmation and some mildburning of the skin.

What is claimed is:

1. A skin depigmenting composition for topical appplication to the skincomprising a melanin inhibiting amount of hydroquinone, retinoic acidand a corticosteroid.

2. A composition according to claim I comprising a melanin inhibitingamount of hydroquinone, retinoic acid, and a corticosteroid selectedfrom the group consisting of dexamethasone, hydrocortisone,hydrocortisonel 7valerate, and progesterone.

3. The composition of claim 2 consisting essentially of from about 2 toabout 5 weight percent hydroquinone, from about 0.05 to about 0.1 weightpercent retinoic acid, and from about 0.05 to about O.l weight percentdexamethasone in a pharmaceutically acceptable vehicle for topicalapplication.

4. A composition according to claim 2 consisting essentially of fromabout 2 to about 5 weight percent hy droquinone, from about 0.05 toabout 0.1 weight percent hydrocortisone-l7-valerate, and from about 0.05to about 0.1 weight percent retinoic acid in a pharmaceuticallyacceptable vehicle for topical application.

5. A method for inhibiting the production of melanin which comprisestopical application of a composition comprising hydroquinone, retinoicacid, and a corticosteroid, in amounts sufficient to causedepigmentation.

and continuing such application until depigmentation is achieved.

8. A method according to claim 5 which comprises topical application topigmented skin of a composition comprising from about 2 to about 5weight percent hydroquinone, from about 0.05 to about 0.1 weight percentretinoic acid, and from about 0.05 to about 0.1 weight percentdexamethasone in a pharmaceutically acceptable vehicle ior iopigcal*application.

1. A SKIN DEPIGMENTING COMPOSITION FOR TOPICAL APPLICATION TO THE SKINCOMPRISING A MELANIN INHIBITING AMOUNT OF HYDROQUINONE, RETINOIC ACIDAND A CORTICOSTEROID.
 2. A composition according to claim 1 comprising amelanin inhibiting amount of hydroquinone, retinoic acid, and acorticosteroid selected from the group consisting of dexamethasone,hydrocortisone, hydrocortisone-17-valerate, and progesterone.
 3. Thecomposition of claim 2 consisting essentially of from about 2 to about 5weight percent hydroquinone, from about 0.05 to about 0.1 weight percentretinoic acid, and from about 0.05 to about 0.1 weight percentdexamethasone in a pharmaceutically acceptable vehicle for topicalapplication.
 4. A composition according to claim 2 consistingessentially of from about 2 to about 5 weight percent hydroquinone, fromabout 0.05 to about 0.1 weight percent hydrocortisone-17-valerate, andfrom about 0.05 to about 0.1 weight percent retinoic acid in apharmaceutically acceptable vehicle for topical application.
 5. A methodfor inhibiting the production of melanin which comprises topicalapplication of a composition comprising hydroquinone, retinoic acid, anda corticosteroid, in amounts sufficient to cause depigmentation.
 6. Themethod of claim 5 wherein said composition consists essentially ofhydroquinone, retinoic acid, and dexamethasone.
 7. A method according toclaim 5 which comprises topical application to pigmented skin of acomposition comprising from about 2 to about 5 weight percenthydroquinone, from about 0.05 to about 0.1 weight percent retinoic acid,and from about 0.05 to about 0.1 weight percenthydrocortisone-17-valerate in a pharmaceutically acceptable vehicle forTopical application and continuing such application until depigmentationis achieved.
 8. A method according to claim 5 which comprises topicalapplication to pigmented skin of a composition comprising from about 2to about 5 weight percent hydroquinone, from about 0.05 to about 0.1weight percent retinoic acid, and from about 0.05 to about 0.1 weightpercent dexamethasone in a pharmaceutically acceptable vehicle fortopical application.